1. Field of the Invention
The present invention relates to bicycloamine derivatives having sodium channel inhibitory action, and particularly 8-azabicyclo[3.2.1]octane or 9-azabicyclo[3.3.1]nonane derivatives or pharmaceutically acceptable salts thereof.
2. Related Background Art
Compounds having sodium channel inhibitory action are known to be useful as treatment for various types of neuralgia (for example, postherpetic neuralgia, diabetic neuralgia, HIV-induced neuralgia and the like).
Compounds having sodium channel inhibitory action include Lidocaine, Carbamazepine, Mexiletine, Amitriptyline and the like, which are already used as therapeutic agents for various types of neuralgia. For example, Lidocaine is used as a treatment for postherpetic neuralgia, and Carbamazepine is used as a treatment for trigeminal neuralgia.
It has also been reported that Mexiletine and Lidocaine are effective as analgesics (see Non-patent documents 1-3, for example).
The following pharmacological activity and therapeutic effects have also been reported for compounds having sodium channel inhibitory action, for diseases other than neuralgia.
(i) Compounds having sodium channel inhibitory action are used as treatments for epilepsy (Non-patent document 4).
(ii) Carbamazepine, used as an anticonvulsant, is effective as a treatment for manic-depressive psychosis (Non-patent document 5).
(iii) Lidocaine and Mexiletine are effective for various symptoms of multiple sclerosis (Non-patent document 6).
(iv) Lidocaine is effective as a treatment for premature ejaculation (Non-patent document 7).
(v) Carbamazepine and Oxocarbazepine used as anticonvulsants also have somnolent action (Non-patent documents 8 and 9), and sodium channel inhibitors can be used as treatments for insomnia.
(vi) Various animal neuropathy models have demonstrated action by sodium channel inhibitors, and suggested protective action against cerebrovascular disease and against neuropathy associated with head injury or spinal cord injury (Non-patent document 10).
(vii) The effectiveness of sodium channel inhibitors in animal models of Parkinson's disease has been reported at an academic meeting (Non-patent document 11).
While sodium channel inhibitors are thus effective as treatments for the diseases mentioned above, sodium channels are also present in non-neuronal tissue such as in the muscles and heart, such that they exhibit side-effects when systemically administered.
Progress in molecular biology has brought to light 10 different sodium channel subtypes with different α-subunits that form the pores of voltage-gated sodium channels. Of these subtypes, Nav1.8 is a tetrodotoxin (TTX)-resistant sodium channel localized in the small neurons of the dorsal root ganglion (C-fibers) that are associated with nerve sensation, and it is referred to as sensory neuron specific sodium channel (SNS) SCN10A or PN3 (Non-patent documents 12 and 13). It has been reported that Nav1.8 knockout mice have an increased nociception threshold for mechanical stimulation (Non-patent document 14), and that administration of antisense DNA for Nav1.8 to neurogenic pain or inflammatory pain models attenuates hyperesthesia and dysesthesia. Therefore, Nav1.8 inhibitors are promising as drugs capable of exhibiting analgesic effects against diseases of neurogenic pain including pain, numbness, burning sensation and dull pain, or nociceptive pain, in which C-fibers are involved. Also, since Nav1.8 is not expressed in non-neuronal tissue or central nerve, drugs that selectively inhibit Nav1.8 are considered to have potential as drugs with no side-effects in non-neuronal tissue or central nerve.
Low molecular compounds having sodium channel inhibitory action have been reported as Nav1.8 inhibitors, but these compounds have different structures than the compounds of the invention (see Patent documents 2-10, for example).
Also, the following 3-azabicyclo[3.3.1]nonane derivative has been reported, and it has a structure similar to a compound of the invention (Patent document 1, Example 129).

This compound has an inhibitory activity against sodium channels in cultured rat hippocampus but its inhibitory activity against ectopic firing is described as inadequate. No bicycloamine compounds other than the 3-azabicyclo[3.3.1]nonane derivative are disclosed in the patent document. Moreover, 8-azabicyclo[3.2.1]octane derivatives and 9-azabicyclo[3.3.1]nonane derivatives having sodium channel inhibitory action are still unknown.    [Patent document 1] WO01/053288    [Patent document 2] US20050020564    [Patent document 3] WO03/037274    [Patent document 4] WO03/037890    [Patent document 5] WO03/037900    [Patent document 6] WO06/082354    [Patent document 7] WO06/113875    [Patent document 8] WO06/132192    [Patent document 9] WO07/052,123    [Patent document 10] WO07/083,239    [Non-patent document 1] Sindrup et al., Pain, 83:389-400, 1999    [Non-patent document 2] Kalso et al., Eur. J. Pain, 2:3-14, 1998    [Non-patent document 3] Kingery et al., Pain, 73:123-139, 1997    [Non-patent document 4] Kwan et al., Pharmacol. Ther., 90:21-34, 2001    [Non-patent document 5] Obrocea et al., Biol. Psychiatry, 51:253-260, 2002    [Non-patent document 6] Sakurai et al., J. Neurol. Sci., 162:162-168, 1999    [Non-patent document 7] Atikeler et al., Andrologia, 34:356-359, 2002    [Non-patent document 8] Nieto-Barrera et al., Epilepsy, 46:145-155, 2002    [Non-patent document 9] Wellington et al., CNS Drugs, 15:137-163, 2001    [Non-patent document 10] Taylor et al., Trends Pharmacol. Sci., 16:309-316, 1995    [Non-patent document 11] Stutzmann et al., 31st Annual Meeting of Society for Neuroscience, Abstract 199.16, 2001    [Non-patent document 12] Akopian et al., Nature, 379:257-262, 1996    [Non-patent document 13] Rabert et al., Pain, 78:107-114, 1998    [Non-patent document 14] Akopian et al., Nat. Neurosci., 2:541-548, 1999